17β-substituted 4-azaandrostane derivatives, pharmaceutical compositions containing them and process for preparing same

ABSTRACT

The invention relates to novel 17β-substituted 4-azaandrostane derivatives of general formula (I), ##STR1## wherein R means hydrogen or a C 1-3  alkyl group; 
     R 1  and R 2  are the same or different and stand for hydrogen or a C 1-4  alkyl group with the proviso that both can mean hydrogen only in the case when n is higher than 5; or 
     R 1  and R 2  together means an α,ω-alkylene group containing 5 to 7 carbon atoms, the terminal carbon atoms of said alkylene group being bound to the same ring carbon atom; 
     n is 4, 5, 6 or 7; and 
     --- bond line represents a single or double bond. 
     Furthermore, the invention relates to pharmaceutical composition containing these compounds as well as a process for the preparation of the compounds of general formula (I). 
     The compounds of general formula (I) exert a 5α-reductase enzyme-inhibiting effect and therefore, they are useful for treating all diseases, where the aim is to reduce the tissue dihydrotestosterone level, such as the benign prostatic hyperplasia, acne, seborrhoea, female hirsutism or androgenic alopecia.

SPECIFICATION

The invention relates to novel 17β-substituted 4-azaandrostanederivatives of formula (I), ##STR2## wherein R means hydrogen or a C₁₋₃alkyl group;

R¹ and R², are the same or different and stand for hydrogen or a C₁₋₄alkyl group with the proviso that both can mean hydrogen only in thecase when n is higher than 5; or

R¹ and R² together means an α,ω-alkylene group containing 5 to 7 carbonatoms, the terminal carbon atoms of said alkylene group being bound tothe same ring carbon atom;

n is 4, 5, 6 or 7; and

--- bond line represents a single or double bond

as well as pharmaceutical compositions containing these compounds.

Furthermore, the invention relates to a process for the preparation ofthe above compounds and compositions.

The compounds of the formula (I) according to the invention are new andpossess a valuable biological activity namely, by inhibiting thefunction of the 5α-reductase enzyme, they impede the transformation oftestosterone to dihydrotestosterone.

Accordingly, the invention relates also to a method of treatment, whichcomprises administering a therapeutically effective amount of a compoundof the formula (I) to a patient to be treated including humans forinhibiting the 5α-reductase enzyme.

BACKGROUND OF THE INVENTION

Among the steroid hormones, the androgens are reponsible for all thephysical characteristics distinguishing male individuals from the femaleones. In male individuals two steroids, testosterone and its reducedmetabolite, i.e. dihydrotestosterone (abbreviated: DHT) are primarilyresponsible for the androgenic effects. In the tissues of mammals, thetransformation of testosterone into DHT is catalyzed by the steroid5α-reductase enzyme in the presence of nicotinamide adenine dinucleotidephosphate (NADPH). In male individuals, testosterone is predominantlysynthetized by the testicles, wherefrom it is carried to the varioustissues by the blood flow. In a part of the androgen-sensitive tissueswhere a significant activity of the steroid 5α-reductase enzyme can bedetected, e.g. in the prostatic and skin tissues, the direct mediator ofthe androgenic effect is dihydrotestosterone which is synthetized insitu from testosterone taken up from the blood flow.

The increase of the DHT concentration in the tissues plays a role in thedevelopment and persistence of a number of androgen-dependent diseases,such as e.g. benign prostatic hyperplasia, acne, seborrhea, femalehirsutism and androgenic alopecia [J. Clin. Invest. 49, 1737 (1970); J.Invest. Dermatol. 56, 366 (1971); J. Endocr. 75, 83 (1977); as well asClin. in Dermatol. 6, 122 (1988)]. All substances inhibiting the steroid5α-reductase enzyme and thereby diminishing the concentration of DHT inthe tissues, may be useful for the treatment of the above DHT-dependentdiseases.

Based on this recognition, research was directed to the synthesis of5α-reductase enzyme inhibitors. In the last fifteen years many5α-reductase enzyme inhibitors containing the steroid skeleton have beendescribed in the literature.

The largest group of 5α-reductase inhibitors known until now isrepresented by the 4-aza-17-carbamoyl steroids.

A compound containing the 4-aza structural moiety is described in theU.S. Pat. No. 4,377,584 and in J. Steroid Biochem. 19, pages 385 to 390(1983).

The synthesis of17β-(N,N-diethylcarbamoyl)-4-methyl-4-aza-5α-androstan-3-one isemphasized in the U.S. Pat. No. 4,220,775. On the basis of literaturedata this compound was subjected to a comprehensive biological study.

The synthesis of novel 17β-(N-monosubstitutedcarbamoyl)-4-aza-5α-androstenones, e.g.17β-[N-(1,1-dimethylethyl)carbamoyl]-3-oxo-4-aza-5α-androst-1-ene[compound of code No. MK-906, named Finasteride] is described in theEuropean patent specification No. 155,096. Nowadays, the above compoundhas been accepted for therapeutical use.

The synthesis of oxidized analogues of 17β-(N-monosubstitutedcarbamoyl)-4-aza-5α-androstan-3-one derivatives are published in theEuropean patent specification No. 271,220. It is characteristic of thecompounds described that the alkyl substituent of the17β-(N-monosubstituted carbamoyl) moiety may bear a hydroxyl, carboxylor alkoxycarbonyl group.

The synthesis and use for the treatment of alopecia of17β-(N-monosubstituted carbamoyl)-4-aza-5α-androst-1-en-3-onederivatives are described in the European patent specification No.285,382; whereas the use of the above compounds for the treatment ofprostate carcinoma is suggested in the European patent specification No.285,383.

A novel process for building-up the aminocarbonyl side chain in position17 of 17β-substituted-3-oxo-4-azasteroids via the Grignard reaction ofthe imidazole derivative of the appropriate carboxylic acid is presentedin the European patent specification No. 367,502.

The European patent specification No. 462,662 discloses the synthesis of17β-(N-monosubstituted adamantylcarbamoyl)- as well as(norbornylcarbamoyl)-4-aza-5α-androst-1-en-3-one and-4-aza-5α-androstan-3-one. In the patent specifications, thepossibilities of use of the 5α-reductase-inhibiting compounds are alsodiscussed.

The synthesis of 4-azasteroids containing double bond(s) in thepositions 8(14), 7(8) or 16(17) and/or 1(2) is described in the Europeanpatent specification No. 277,002. A characteristic structural moiety ofthe C₁₇ -side chain is the aminocarbonyl group, but another side chaincontaining oxygen or nitrogen may also be present in position 17.

The combination of aromatase inhibitors with 5α-reductase inhibitors issuggested for the treatment of prostatic hyperplasia in the Germanpatent specification No. 3,607,651.1-Methylandrosta-1,4-diene-3,17-dione as aromatase inhibitor and17β-(N,N-diethylcarbamoyl)-4-methyl-4-aza-5α-androstan-3-one as5α-reductase inhibitor are recommended.

The topical usability of 5α-reductase inhibitors is suggested in theU.S. Pat. No. 4,885,289.

In the PCT patent application published under No. WO 91/12261, thesynthesis of 4-azasteroids is disclosed, the C₁₇ -side chain of which isdifferent from those previously described. A characteristic example ofthese compounds is4-methyl-17β-[N-isopropyl-N-(N,N-diisopropylcarbamoyl)carbamoyl]-4-aza-5α-androstan-3-one.

The synthesis of novel 4-azasteroids bearing a C₁₇ -side chain offormula --X--COZ is published in the European patent specification No.200,859. In this formula X means a chemical bond or a straight orbranched C₁₋₆ aliphatic chain and Z stands for an alkoxy or asubstituted amino group. These compounds may contain also an oxo groupin position 12 of the steroid skeleton.

The Hungarian patent application No. 3396/91 (published under No.T/59417) relates to the synthesis of 4-azasteroid derivatives containinga C₁₇ -aminocarbonyl side chain bearing an alkyl group substituted by anaromatic group. These compounds are useful for the treatment andprevention of prostatic hypertrophia.

Various types of azasteroids mainly inhibiting 5α-reductase issummarized in J. Med. Chem. 27, pages 1690 to 1701 (1984). This summarycontains biological data, too.

The structure-activity relationship of 5α-reductase inhibitorscontaining the 4-aza structural moiety is discussed in J. Med. Chem. 29,pages 2298 to 2315 (1986).

The 5α-reductase-inhibiting activity and the biological effect ofantiandrogenic properties of 4-azasteroids observed on rats aresummarized in Steroids 47/1, pages 1 to 19 (1986).

The transformation of acylimidazole derivatives, mainly to carboxamidederivatives is published in Synt. Comm. 30(17), pages 2683 to 2960(1990).

The high number of the above-cited literature and patent documents alsosupport the importance of 5α-reductase inhibitors.

OBJECT OF THE INVENTION

The object of the present invention is to prepare new compounds, whichshow a higher biological effectivity in comparison to those known fromthe prior art and/or exert a more selective inhibitory effect on theactivity of the 5α-reductase enzyme. Namely, the properties mentionedabove may result in a more advantageous therapeutical utilization thanthe known drugs.

SUMMARY OF THE INVENTION

It has surprisingly been found that the 5α-reductase-inhibiting actioncan significantly be enhanced by the specific selection of theaminocarbonyl substituent in position 17 of 17β-substituted4-azaandrostene and -androstane derivatives of formula (I) according tothe present invention.

According to the invention the preparation of the novel compounds ofgeneral formula (I) comprises

reacting a 17-halogeno-4-azaandrostene derivative of general formula(II) ##STR3## wherein the and ---- bond line are as defined above and Xstands for chlorine, bromine or iodine, with a cyclic amine of generalformula (III), ##STR4## wherein R¹, R² and n are as defined above, in adipolar aprotic solvent in the presence of a palladium(II) salt, atertiary amine base and phosphines, or in the presence of apalladium(II) complex and a tertiary amine base, in a carbon monoxideatmosphere at a temperature between 35° C. and 80° C.; and

if desired, dehydrogenating an obtained compound of the formula (I),wherein R, R¹, R², the ---- bond line between the C₅ and C₆ atoms aswell as n are as defined above, containing a double bond between the C₁₆and C₁₇ atoms as well as a single bond between the C₁ and C₂ atoms toobtain a compound of the formula (I) containing double bonds between theC₁ and C₂ atoms as well as between C₁₆ and C₁₇ atoms, wherein R, R¹, R²,the ---- bond line between C₅ and C₆ atoms and n are as defined above;and/or

if desired, transforming by catalytical hydrogenation an obtainedcompound of the formula (I), wherein R, R¹, R², n, the ---- bond linebetween the C₅ and C₆ atoms as well as between the C₁ and C₂ atoms areas defined above, containing a double bond between the C₁₆ and C₁₇atoms, to obtain a compound of the formula (I) containing a single bondas the ---- bond line wherein R, R¹, R² and n are as defined above;and/or

if desired, dehydrogenating an obtained compound of the formula (I),wherein R, R¹, R² and n are as defined above, containing single bondsbetween the C₁ and C₂ atoms, C₅ and C₆ atoms, as well as C₁₆ and C₁₇atoms, to obtain a compound of the formula (I), containing a double bondbetween the C₁ and C₂ atoms, wherein R, R¹, R² and n are as definedabove and the ---- bond line means single bonds between the C₅ and C₆ aswell as C₁₆ and C₁₇ atoms.

In the reaction of the compounds of the formula (II) with the compoundsof the formula (III), preferably palladium(II) diacetate or dichlorideas palladium(II) salts, triethylamine as a tertiary amine base andtriphenylphosphine, 1,4-bis-(diphenylphosphino)butane,1,2-bis(diphenylphosphino)ethane or 1,3-bis(diphenylphosphino)propane asphosphines are employed. The reaction may be carried out also in such away that a complex of a palladium (II) salt formed with a phosphine,e.g. [bis(triphenylphosphino)palladium(II)]dichloride or diacetate maybe used instead of a palladium(II) salt and phosphines.

In the above reaction, a dipolar aprotic solvent, suitablydimethylformamide or dimethylsulfoxide may be used as solvent.

The compounds of the formula (I) obtained in the above reaction can besubjected to further transformations within the scope of the generalformula (I).

Thus, an obtained compound of the formula (I) containing a double bondbetween the C₁₆ and C₁₇ atoms and a single bond between C₁ and C₂ atomsmay be dehydrogenated to a compound of the formula (I) containing doublebonds both between the C₁ and C₂ atoms as well as C₁₆ and C₁₇ atoms.

This dehydrogenation can preferably be performed by using a quinone typesubstance, e.g. 2,3-dichloro-5,6-dicyano-1,4-benzoquinone in thepresence of a silylating agent such asbis(trimethylsilyl)-trifluoroacetamide or with phenylselenic acidanhydride.

Another possibility for the subsequent transformation is providedthereby that an obtained compound, wherein R, R¹, R² and the ---- bondline between the C₁ and C₂ atoms as well as C₅ and C₆ atoms and n are asdefined above, containing a double bond between the C₁₆ and C₁₇ atomscan be transformed by catalytic hydrogenation to a compound of theformula (I), containing a single bond as ---- bond line, wherein R, R¹,R² and n are as defined above As another additional transformation, ifdesired, the thus obtained compounds may be dehydrogenated in thepositions 1-2 as described above.

According to a preferred embodiment of the process of the presentinvention a 17-halogeno-4-azaandrostene derivative of the formula (II)is reacted with an amine of the formula (III), e.g. hexamethyleneimine,heptamethyleneimine, 4-methylpiperidine, 3,3-dimethylpiperidine,2,6-dimethylpiperidine, 2,5-dimethylpyrrolidine or3-azaspiro[5,5]undecane in dimethylformamide, in the presence ofpalladium(II) diacetate, triphenylphosphine and triethylamine undercarbon monoxide atmosphere at a temperature of 60° C. for 1.5 to 2hours.

After the reaction becomes complete, the amines and dimethylformamideare distilled off under reduced pressure. The residue is dissolved inchloroform and successively washed with water, aqueous hydrochloric acidsolution, aqueous sodium hydrogen carbonate solution and again withwater until neutral. After drying, the solvent is distilled off and theresidue is purified by chromatography or recrystallization or by usingboth methods together.

The obtained 4-aza-17-carboxamido derivatives of the formula (I)containing a double bond between the C₁₆ and C₁₇ atoms and a single ordouble bond between the C₅ and C₆ atoms can be dehydrogenated in thepositions 1-2 of the steroid skeleton by using quinones in the presenceof a silylating agent or by an other method, e.g. with phenylselenicacid anhydride.

According to the present invention the following procedure is preferablyfollowed. Toluene, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone,bis(trimethylsilyl)-trifluoroacetamide and a catalytic amount oftrifluoroacetic acid are added to the compound of the formula (I) to bedehydrogenated. The reaction mixture is stirred under nitrogen at roomtemperature for 18 hours, meanwhile the progress of the reaction may befollowed by liquid chromatography. After disappearance of the startingsubstance, cyclohexane-1,3-dione is added to the reaction mixture, whichis then stirred for an additional 3 hours in order to decompose theexcess of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone. Then, the reactionmixture is gently boiled under reflux for 20 hours. During this periodthe adduct is decomposed and a double bond is formed between the C₁ andC₂ atoms of the steroid skeleton. To the toluene solution after coolingdown, methylene chloride is added and the mixture is stirred withsaturated sodium hydrogen carbonate solution. After separating, theorganic phase is again extracted with sodium hydrogen carbonatesolution. After drying, the solvent is removed under reduced pressureand the residue is purified by recrystallization.

For obtaining saturated compounds of general formula (I), theunsaturated compounds obtained are hydrogenated.

The catalytic hydrogenation may be carried out e.g. in the presence ofcharcoal supported palladium and hydrogen gas, in alcoholic solution; orin the presence of charcoal-supported palladium catalyst in formic acidmedium; or by using platinum(IV) oxide catalyst and hydrogen in glacialacetic acid medium.

In the former case, for example, the unsaturated compound of the formula(I) is dissolved in ethanol and hydrogenated in the presence ofcharcoal-supported palladium catalyst and hydrogen gas under atmosphericpressure at room temperature. After the reaction becomes complete, thecatalyst is filtered off, and after evaporating the solvent the residueis purified by recrystallization.

The double bonds may be saturated also in such a manner that theunsaturated compounds of the formula (I) are dissolved in formic acidand then hydrogenated in the presence of a charcoal supported palladiumcatalyst; or after dissolving in glacial acetic acid the unsaturatedcompound may be hydrogenated by using platinum oxide catalyst underhydrogen atmosphere. After filtering off the catalyst, the formic acidor acetic acid used as solvent is distilled off and the residue ispurified by recrystallization or chromatography.

By carrying out the hydrogenating and dehydrogenating steps in asuitable succession order compounds of the formula (I) can be prepared,which contain a double bond only between the C₁ and C₂ atoms. To thispurpose, a compound of the formula (I) containing double bond(s),obtained from the reaction of the compounds of the formulae (II) and(III) is saturated by hydrogenation as described above, then theobtained saturated compound of the formula (I) is dehydrogenated in 1-2positions as described above.

17-Halogeno-4-azaandrostene derivatives of the formula (II) used asstarting substances for the preparation of compounds of the formula (I)may be synthetized by using the known 4-aza-5α-androstane-3,17-dione,4-aza-androst-5-ene-3,17-dione or their N-alkyl derivatives [J. Pharm.Sci. 63, pages 19 to 23 (1974); J. Med. Chem. 27, 1690 (1984); J. Org.Chem. 46, pages 1442 to 1446 (1981)] as follows.

After dissolving the known 4-aza-5α-androstane-3,17-dione,4-azaandrost-5-ene-3,17-dione or their N-alkyl derivatives, respectivelyin ethanol, triethylamine and hydrazine hydrate are added to the abovesolution and the reaction mixture is boiled under reflux. After completereaction the excess of hydrazine hydrate and triethylamine are distilledoff, the residue is precipitated with water, and after filtering off,the precipitate is washed with water until neutral and dried. The thusobtained crude 17-hydrazono derivatives are used after or withoutpurification to prepare the 17-halogeno-4-azaandrostene derivatives ofthe formula (II).

Compounds of the formula (II) containing iodine as X are prepared insuch a way that the 17-hydrazono derivatives obtained in the precedingstep are reacted with iodine at room temperature in a halogenatedhydrocarbon and/or aromatic solvent in the presence of a tertiary aminebase. After complete reaction the tertiary amine base and excess iodineare removed by treatment with dilute aqueous hydrochloric acid solutionand then with sodium thiosulfate. After evaporating the solvent, theresidue is purified by recrystallization or chromatography.

Compounds of the formula (II) containing chlorine or bromine as X areprepared from the 17-hydrazono derivatives in such a way that the17-hydrazono derivative is dissolved in pyridine and N-chloro- orN-bromosuccinimide is portionwise added to the above solution at about-10° C. temperature. After complete reaction the crude product isprecipitated with water and filtered off. The precipitate is washeduntil it becomes free from pyridine, then dried and finally purified byrecrystallization or chromatography.

The 5α-reductase-inhibiting activity of 4-aza-5α-androstene derivativesof the formula (I) according to the invention was studied by using astandardized in vitro method as follows.

Preparation of the Steroid 5α-reductase Enzyme

Frozen human hyperplastic prostate was used for preparation of theenzyme. The low-frozen prostate was thawed in a 20 mM potassiumphosphate buffer (pH=6.6) containing 320 mM saccharose, 1 mMdithiothreitol and 50 μM NADPH (solution A) at 0° C., then purified andcut into pieces of 2 to 3 mm³ size by shears. The chopped tissue wasthen homogenized at 0° C. in solution A having a 4 to 5-fold volume ofthe prostate in an Ultra turrax homogenizer (Janke and Kunkel,Ika-Werk), then the homogenate was rubbed through a plastic filter of0.5 mm pore size. The thus obtained prostate suspension was furtherground for 5 minutes by using supersound and the cell debris waspurified by two ultracentrifugations (100000×g, 1 hour at 0° C.). Thecell debris settling in the second centrifugation was suspended in atwofold tissue volume of 20 mM potassium phosphate buffer of 0° C.(pH=6.6) containing 20% of glycerol and 1 mM of dithiothreitol.Thereafter, the suspension was filtered through a plastic filter of 0.5mm pore size and stored in divided portions at -70° C. until the use.

Measurement of the 5α-reductase Inhibition

In the routine investigation of enzyme inhibition, the reaction mixturecontained 0.5 μM [³ H]-testosterone (with a specific activity of 2.7GBq/mmol), 1 mM dithiothreitol, 500 μM NADPH, 40 mM TRIS citrate buffer(pH=5.1) and enzyme preparation containing 0.5 to 0.6 mg of protein in avolume of 0.5 ml. ["TRIS" is the abbreviation oftris(hydroxymethyl)aminomethane]. The substances under test dissolved in5 μl of ethanol were added to the incubation system in an amountsufficient to reach a final concentration of 10⁻⁶ to 10⁻⁹ M of thesubstances in the reaction mixture. The control samples also contained 5μl of ethanol. After incubating the samples at 37° C. for 10 minutes(the enzyme reaction was linear for 20 minutes) the activity of theenzyme was stopped by adding 2 ml of ethyl acetate. Subsequently, thesteroids (testosterone, DHT, androstanediol) were extracted with anorganic solvent and then separated on a Poligram Sil G/UV 254 (MachereyNagel) thin layer chromatography (TLC) sheet by using twofolddevelopment with a 198:3 mixture of chloroform/methanol. For visualizingthe steroid spots on the TLC sheet, 12 μg of testosterone, DHT andandrostanediol each were added to the samples during the extraction.After the TLC separation the steroid spots were cut out and thepercentage conversion of testosterone to DHT and androstanediol (whichlatter is the chief metabolite of DHT) were determined on the bases oftheir radioactivity measured by liquid scintillation method. The5α-reductase-inhibiting activity of the substances under test wascharacterized by their concentration (IC₅₀ value) decreasing thepercentage conversion of testosterone by 50% in comparison to thecontrol value.

In these investigations17β-[N-(1,1-dimethylethyl)carbamoyl]-3-oxo-4-aza-5α-androst-1-ene(compound MK-906, Finasteride) developed by Merck Sharp and DohmeCompany (United States) was used as reference substance. The results ofthe comparative tests are shown in the following Table.

                  TABLE                                                           ______________________________________                                        Compound               IC.sub.50                                              ______________________________________                                        17β-[N-(1,1-Dimethylethyl)carbamoyl]-                                                           1.84 × 10.sup.-8 M                               3-oxo-4-aza-5α-androst-1-ene (MK-906)                                   17β-(2,6-Dimethylpiperidinocarbonyl)-                                                           8.59 × 10.sup.-9 M                               3-oxo-4-aza-5α-androst-1-ene                                            17β-(Hexamethyleneiminocarbonyl)-3-                                                             1.31 × 10.sup.-8 M                               oxo-4-aza-5α-androst-1-ene                                              17β-(Heptamethyleneiminocarbonyl)-3-                                                            8.64 × 10.sup.-9 M                               oxo-4-aza-5α-androst-1-ene                                              ______________________________________                                    

It can be seen from the data that the compounds of the formula (I)according to the invention posses a stronger 5α-reductase-inhibitingactivity in comparison to17β-[N-(1,1-dimethylethyl)carbamoyl]-3-oxo-4-aza-5α-androst-1-ene usedas reference substance.

Based on their steroid 5α-reductase-inhibiting activity, the compoundsof the formula (I) of the present invention are useful for the treatmentof all diseases where the therapeutic aim is to decrease the tissueconcentration of DHT. Diseases of such kind are, e.g., the benignprostatic hyperplasia, acne, seborrhea, female hirsutism and androgenicalopecia.

The compounds of the formula (I) of the invention can preferably be usedfor treating the benign prostatic hyperplasia. The compounds can beadministered in various ways to the patients in order to achieve theeffect desired. In connection with the treatment of benign prostatichyperplasia, "patients" are meant to be warm-blooded male animals suchas male dogs as well as male humans.

The compounds of the invention can be administered alone or incombination with other compounds. Preferably, the compounds can beadministered in the form of pharmaceutical compositions in oral orparenteral, e.g., intravenous, intraperitoneal, intramuscular orsubcutaneous routes including the direct injection of the active agentto the prostate. Pharmaceutical compositions as implants with sustainedrelease may also be employed. The amount to be used of the compounds canbe varied under wide limits and may be any effective amount. Dependingon the patient to be treated, severity of the disease treated and routeof the administration, the effective amount of the compounds may beabout daily 0.001 to 10 mg/kg of body weight.

Pharmaceutical compositions useful for oral or parenteral administrationmay contain, e.g., 0.1 to 100 mg of a compound according to theinvention. The dosage limits defined for the compounds of the inventionare useful for diminishing the size of prostate, i.e., they represent anamount being effective for the treatment of benign prostatichyperplasia. The compounds according to the invention can be used forthe treatment of the developed disease (benign prostatic hyperplasia) orfor treating the symptoms induced by the disease, respectively; however,they can be employed for a prophylactic therapy, too.

The compounds according to the invention can be used also for thetreatment of acne, seborrhea, androgenic alopecia or female hirsutism.In these cases the compounds may be administered topically, orally,parenterally, e.g., intramuscularly or subcutaneously. It is suitable toemploy a topical treatment. Here, the patients to be treated may be anymammal, e.g. primate, such as human and within this men or women. Thecompounds may be used alone or in combination with other compounds inthe form of suitable pharmaceutical compositions. The amount to be usedof the active agent depends on the manner of treatment, state of thepatient as well as the severity of the disease (acne, seborrhea,androgenic alopecia, female hirsutism). For oral and parenteraladministration the effective dose of the compound may be about daily0.001 to 10 mg/kg of body-weight. In these routes of administration thepharmaceutical compositions may contain 0.1 to 100 mg of a compound ofthe invention as active ingredient. For topical administration theactive ingredient content of the composition can be varied from 0.001%up to 5%. When administered topically, the active ingredient may bedirectly applied onto the site to be treated or onto the oral or nasalmucosa.

The invention also relates to a method for inhibiting the activity ofthe 5α-reductase enzyme in mammals including humans. This methodcomprises administering a therapeutically effective amount of activeagent of the the formula (I) to the patient.

The invention is illustrated in detail by the following non-limitingExamples.

EXAMPLE 1 Preparation of 17-hydrazono-4-aza-5α-androstan-3-one

To a suspension of 10 g (0.0346 mol) of 4-aza-5α-androstane-3,17-dionein 100 ml of ethanol 14 ml (0.1 mol) of triethylamine and 50 ml (1.0mol) hydrazine hydrate are added and the mixture is boiled under refluxfor 3 hours. [The progress of the reaction is followed by thin layerchromatography (TLC)]. After complete reaction the mixture is cooleddown, the solution is evaporated to one tenth of its original volume andthen, the product is precipitated by adding about 10-fold volume ofwater. After compaction the precipitate is filtered, washed with wateruntil neutral and dried to obtain the title compound in a yield of 9.44g (90%), m.p.: 254°-258° C.

¹ H-NMR (300 MHz, CDCl₃) δ ppm: 0.86 (s,3H,18-CH₃), 0.93 (s,3H,19-CH₃),2.41 (m,2H,H-2), 3.07 (dd,1H,H-5), 4.77 (br,2H,NH₂), 5.74 (br,1H,NH).

EXAMPLE 2 Preparation of 17-hydrazono-4-azaandrost-5-en-3-one

The process of Example 1 is followed, except that4-azaandrost-5-ene-3,17-dione is used as starting material to give thetitle compound in a yield of 35%, m.p.: 379°-382° C.

IR [KBr, ν(cm⁻¹)]: 1633 (C═C), 1661 (C═N), 1693 (C═O), 3200 (NH), 3350(NH₂).

EXAMPLE 3 Preparation of 17-hydrazono-4-methyl-4-aza-5α-androstan-3-one

The process of Example 1 is followed, except that4-methyl-4-aza-5α-androstane-3,17-dione is used as starting material toobtain the title compound in a yield of 75%, m.p.: 211°-218° C.

¹ H-NMR (300 MHz, CDCl₃) δ ppm: 0.86 (s,3H,18-CH₃), 0.91 (s,3H,19-CH₃),2.93 (s,3H,N-CH₃), 3.05 <dd(J=3.6;J=12.6),1H,H-5>, 4.78 (vbr, 2H, NH₂).

EXAMPLE 4 Preparation of 17-iodo-4-aza-5α-androst-16-en-3-one A.)

After dissolving 9.1 g (0.03 mol) of17-hydrazono-4-aza-5α-androstan-3-one in 1200 ml of an 1:1chloroform/benzene mixture and then adding 90 ml of triethylamine, 11.4g (0.045 mol) of iodine dissolved in 110 ml of benzene are dropwiseadded to the above solution, which is then stirred an additional 60-90minutes at room temperature. (The progress of the reaction is followedby TLC method). After the reaction has become complete, the solution isdiluted with 500 ml of chloroform, successively washed with 10% aqueoushydrochloric acid solution, water, 5% aqueous sodium thiosulfatesolution, water, finally with 5% aqueous sodium hydrogen carbonatesolution and water, then dried over anhydrous sodium sulfate. Afterevaporating the solvents under reduced pressure, the residue is purifiedby chromatography on a silica gel column by using chloroform andchloroform/acetone mixture as eluents. The product obtained isrecrystallized from ethanol to give the title compound in a yield of 5.9g (50%).

B.)

The preceding procedure is followed, except that tetramethylguanidine isused as base instead of triethylamine. In this way the title compound isproduced in a yield of 65%, m.p.: 278°-282° C.

¹ H-NMR (300 MHz, CDCl₃) δ ppm: 0.73 (s,3H,18-CH₃), (0.91 (s,3H,19-CH₃),3.1 (dd,1H,H-5), 6.18 (m, 1H,H-16), 6.9 (br, 1H,NH).

EXAMPLE 5 Preparation of 17-iodo-4-azaandrosta-5,16-dien-3-one

The process of Example 4 A.) is followed, except that17-hydrazono-4-azaandrost-5-en-3-one is used as starting substance togive the title compound in a yield of 57%, m.p.: 227°-230° C.

¹ H-NMR (300 MHz, CDCl₃) δ ppm: 0.78 (s,3H,18-CH₃), 1.13 (s,3H,19-CH₃),4.9 <dd(J=2.4; J=5.1),1H,H-6>, 6.15 <dd(J=3,2;J=1.7), 1H,H-16), 8.27(br,1H,NH).

EXAMPLE 6 Preparation of 17-iodo-4-methyl-4-aza-5α-androst-16-en-3-one

The process of Example 4 A.) is followed, except that17-hydrazono-4-methyl-4-aza-5α-androstan-3-one is used as startingsubstance and benzene is used as solvent to obtain the title compound ina yield of 52% m.p.: 176°-181° C.

¹ H-NMR (300 MHz, CDCl₃) δ ppm: 0.74 (s,3H,18-CH₃), 0.92 (s,3H,19-CH₃),2.94 (s,3H,N-CH₃), 3.07 <dd (J=3.7; J=12.6), 1H,H-5>, 6.13 <dd(J=3.2;J=1.7),1H,H-16).

EXAMPLE 7 Preparation of 17-chloro-4-methyl-4-aza-5α-androst-16-en-3-one

After dissolving 4 g (0.0126 mol) of17-hydrazono-4-methyl-4-aza-5α-androstan-3-one in 40 ml of anhydrouspyridine and cooling down the solution to 0° C., a solution of 3.2 g(0.024 mol) of N-chlorosuccinimide dissolved in 40 ml of pyridine areadded dropwise under vigorous stirring. After cessation of the violentnitrogen evolution, the reaction mixture is stirred an additional 15minutes and then dropped into 800 ml of water. After compaction of theprecipitate the crude product is filtered off, washed with water untilneutral and dried over phosphorus pentoxide at room temperature underreduced pressure. The crude product obtained is purified bychromatography on a silica gel column by using chloroform as eluent.After recrystallization of the evaporation residue from petroleum ether,the title compound is obtained in a yield of 2.15 g (53%), m.p.:139°-140° C.

¹ H-NMR (60 MHz, CDCl₃) δ ppm: 0.88 (s,3H,18-CH₃), 0.93 (s,3H,19-CH₃),2.89 (s,3H,N-CH₃), 3.0 (dd,1H,H-5), 5.53 (m,1H,H-16).

EXAMPLE 8 Preparation of 17-bromo-4-methyl-4-aza-5α-androst-16-en-3-one

The process of Example 7 is followed, except that similarly,17-hydrazono-4-methyl-4-aza-5α-androstan-3-one is used as startingsubstance but N-bromosuccinimide is employed as reagent to obtain thetitle compound in a yield of 55%, m.p. 159°-161° C.

¹ H-NMR (60 MHz, CDCl₃) δ ppm: 0.82 (s,3H,18-CH₃), 0.91 (s,3H,19-CH₃),2.86 (s,3H,N-CH₃), 3.0 (dd, 1H,H-5), 5.68 (m, 1H,H-16).

EXAMPLE 9 Preparation of17β-(2,6-dimethylpiperidinocarbonyl)-3-oxo-4-aza-5α-androst-16-ene

After dissolving 3.99 g (0.01 mol) of17-iodo-4-aza-5α-androst-16-en-3-one in 150 ml of dimethylformamide,0.224 g (0.001 mol) of palladium(II) diacetate, 0.524 g (0.002 mol) oftriphenylphosphine, 10 ml of triethylamine and 18.9 ml (0.14 mole) ofcis-2,6-dimethylpiperidine are added to the above solution which is thenmaintained under a carbon monoxide atmosphere at 60° C. for 1.5 to 2hours. (The progress of the reaction is followed by TLC and gaschromatography.) After complete progress of the reaction the amines anddimethylformamide (abbreviated: DMF) are distilled off under reducedpressure, the residue is dissolved in 150 ml of chloroform andsuccessively washed with water, 5% aqueous hydrochloric acid solution,saturated aqueous sodium hydrogen carbonate solution and finally withsaturated aqueous saline solution until neutral. The chloroform solutionis dried over anhydrous sodium sulfate and after filtering off thedrying agent and evaporating the solvent, the residue is purified bychromatography on a silica gel column by using ethyl acetate as eluentto obtain the title compound in a yield of 3.50 g (85%), m.p.: 307°-309°C.

¹ H-NMR (60 MHz, CDCl₃) δ ppm: 0.94 (s,3H,19-CH₃); 1.09 (s,3H,18-CH₃);1.24 (d,6H,CH-CH₃); 2.04 and 2.23 (2*m,2H,H-15); 2.40 (m,2H,H-2); 3.07(dd,1H,H-5); 3.95-5.05 (vbr,2H,NCH-CH₃); 5.70 (m,1H,H-16); 6.20(br,1H,NH).

EXAMPLE 10 Preparation of17β-(2,5-dimethylpyrrolidinocarbonyl)-3-oxo-4-aza-5α-androst-16-ene

The process of Example 9 is followed by using17-iodo-4-aza-5α-androst-16-en-3-one as starting substance and2,5-dimethylpyrrolidine as reactant to obtain the title compound in ayield of 95%, m.p.: 281°-286° C.

EXAMPLE 11 Preparation of17β-(heptamethyleneiminocarbonyl)-3-oxo-4-aza-5α-androst-16-ene

The process of Example 9 is followed by using17-iodo-4-aza-5α-androst-16-en-3-one as starting substance withheptamethyleneimine as reactant to give the title compound in a yield of88%, m.p.: 282°-285° C.

EXAMPLE 12 Preparation of17β-(2,6-dimethylpiperidinocarbonyl)-3-oxo-4-aza-5α-androstane

After dissolving 2 g (0.0048 mol ) of17β-(2,6-dimethylpiperidinocarbonyl)-3-oxo-4-aza-5α-androst -16-ene in80 ml of formic acid, a suspension containing 2 g of charcoal-supportedpalladium catalyst in 12 ml of water is added under nitrogen and theheterogeneous reaction mixture is stirred at room temperature for 4 to 5hours. (The progress of the reduction is followed by TLC method.) Aftercomplete progress of the reaction the catalyst is filtered off andwashed with an 1:1 mixture of chloroform and methanol. After evaporatingthe combined solution to dryness, the residue is thoroughly trituratedwith water, the precipitate is filtered and washed with water to givethe title compound in a yield of 1.74 g (87%), m.p.: 300°-303° C.

The title compound has been prepared also by hydrogenating17β-(2,6-dimethylpiperidinocarbonyl)-3-oxo-4-azaandrosta-5,16-diene asdescribed above to obtain a yield of 70%.

¹ H-NMR (300 MHz, CDCl₃) δ ppm: 0.71 (s,3H,18-CH₃); 0.90 (s,3H,19-CH₃);1.18 and 1.20 (2*d,6H,CH-CH₃); 2.40 (m,2H,H-2); 2.71 (t,1H,H-17); 3.04(dd,1H,H-5); 4.28 and 4.73 (2*m,2H,NCH-CH₃); 6.12 (br,1H,NH).

EXAMPLE 13 Preparation of17β-(2,5-dimethylpyrrolidinocarbonyl)-3-oxo-4-aza-5α-androstane

A solution containing 2 g (0.005 mol) of17β-(2,5-dimethylpyrrolidinocarbonyl)-3-oxo-4-aza-5α-androst-16-ene in140 ml of ethanol is hydrogenated in the presence of 0.5 g of charcoalsupported palladium catalyst under atmospheric pressure for 5 to 8hours. (The progress of the reaction is followed by TLC method.) Aftercomplete hydrogenation and filtering off the catalyst, the solution isevaporated to give 1.9 g (95%) of the title compound, m.p.: 295°-300° C.

¹ H-NMR (300 MHz, CDCl₃) δ ppm: 0.79 (s,3H,18-CH₃); 0.90 (s,3H,19-CH₃);1.18 and 1.31 (2*d,6H,CH-CH₃); 2.40 (m,2H,H-2); 2.53 (t,1H,H-17); 3.05(dd,1H,H-5); 4.11 (m,2H,NCH-CH₃); 6.27 (br,1H,NH).

EXAMPLE 14 Preparation of17β-(heptamethyleneiminocarbonyl)-3-oxo-4-aza-5α-androstane

The process of Example 13 is followed, except that17β-(heptamethyleneiminocarbonyl)-3-oxo-4-aza-5α-androst-16-ene is usedas starting substance to obtain the title compound in a yield of 85%,m.p.: 256°-266° C.

¹ H-NMR (60 MHz, CDCl₃) δ ppm: 0.82 (s,3H,18-CH₃); 0.91 (s,3H,19-CH₃);2.8-4.1 (m,5H,H-5 and NCH₂); 6.69 (br,1H,NH).

EXAMPLE 15 Preparation of17β-(hexamethyleneiminocarbonyl)-3-oxo-4-aza-5α-androstane

The process of Example 13 is followed, except that17β-(hexamethyleneiminocarbonyl)-3-oxo-4-aza-5α-androst-16-ene is usedas starting substance to give the title compound in a yield of 86%,m.p.: 276°-281° C.

EXAMPLE 16 Preparation of17β-(4-methylpiperidinocarbonyl)-3-oxo-4-aza-5α-androstane

The process of Example 12 is followed, except that17β-(4-methylpiperidinocarbonyl)-3-oxo-4-aza-5α-androst-16-ene is usedas starting substance to obtain the title compound in a yield of 83%,m.p.: 314°-319° C.

EXAMPLE 17 Preparation of17β-(2,6-dimethylpiperidinocarbonyl)-3-oxo-4-aza-5α-androst-1-ene

To a suspension containing 2.07 g (0.005 mol) of17β-(2,6-dimethylpiperidinocarbonyl)-3-oxo-4-aza-5α-androstane in 24 mlof toluene, 1.25 g (0.0055 mol) of2,3-dichloro-5,6-dicyano-1,4-benzoquinone are portionwise added during30 minutes, then the reaction mixture is stirred under nitrogen anadditional 30 minutes. Subsequently, 5.5 ml (0.021 mol) ofbis(trimethylsilyl)-trifluoroacetamide are dropwise added to thesuspension during 20 to 30 minutes and after termination of theportionwise addition, 2 drops of trifluoroacetic acid are added, thenthe mixture is stirred at room temperature for 20 hours. (The progressof the reaction is followed by TLC method.) After complete progress ofthe reaction 0.05 g (0.0005 mol) of 1,3-cyclohexanedione are added tothe reaction mixture which is then stirred at room temperature anadditional 3 hours and subsequently boiled under reflux for 18 to 20hours. After diluting with 6 ml of methylene chloride, the reactionmixture is washed with sodium hydrogen carbonate solution, dried overanhydrous sodium sulfate and the solvents are removed under reducedpressure. After recrystallization of the residue from ethyl acetate thetitle compound is obtained in a yield of 1.44 g (70%), m.p.: 288°-292°C.

¹ H-NMR (300 MHz, CDCl₃) δ ppm: 0.72 (s,3H,18-CH₃); 0.97 (s,3H,19-CH₃);1.19 and 1.21 (2,d,6H,CH-CH₃); 2.73 (t,1H,H-17); 3.32 (m,1H,H-5); 4.28and 4.73 (2*m,2H,NCH-CH₃); 5.80 (dd,1H,H-2); 6.02 (br,1H,NH); 6.77(d,1H,H-1).

EXAMPLE 18 Preparation of17β-(2,5-dimethylpyrrolidinocarbonyl)-3-oxo-4-aza-5α-androst-1-ene

The process of Example 17 is followed, except that17β-(2,5-dimethylpyrrolidinocarbonyl)-3-oxo-4-aza-5α-androstane is usedas starting substance to give the title compound in a yield of 67%,m.p.: 291°-295° C.

¹ H-NMR (300 MHz, CDCl₃) δ ppm: 0.80 (s,3H,18-CH₃); 0.97 (s,3H,19-CH₃);1.19 and 1.31 (2*d, 6H,CH-CH₃); 2.54 (t,1H,H-17); 3.32 (m,1H, H-5); 4.12(m,2H,NCH-CH₃); 5.80 (dd,1H,H-2); 6.03 (br,1H,NH); 6.77 (d,1H,H-1).

EXAMPLE 19 Preparation of17β-(heptamethyleneiminocarbonyl)-3-oxo-4-aza-5α-androst-1-ene

The process of Example 17 is followed, except that17β-(heptamethyleneiminocarbonyl)-3-oxo-4-aza-5α-androstane is used asstarting substance to obtain the title compound in a yield of 72%, m.p.:278°-281° C.

¹ H-NMR (60 MHz, CDCl₃) δ ppm: 0.82 (s,3H,18-CH₃); 0.98 (s,3H,19-CH₃);2.66 (t,1H,H-17); 3.32 (m,5H,H-5); 3.07-3.3 and 3.63-3,86 (m,4H,NCH₂);5.80 (dd,1H,H-2); 6.02 (br,1H,NH); 6.78 (d,1H,H-1).

EXAMPLE 20 Preparation of17β-(hexamethyleneiminocarbonyl)-3-oxo-4-aza-5α-androst-1-ene

The process of Example 17 is followed, except that17β-(hexamethyleneiminocarbonyl)-3-oxo-4-aza-5α-androstane is used asstarting substance to obtain the title compound in a yield of 71%, m.p.:270°-273° C.

¹ H-NMR (60 MHz, CDCl₃) δ ppm: 0.81 (s,3H,18-CH₃); 0.98 (s,3H,19-CH₃);2.9-4.1 (m,5H,H-5 and NCH₂); 5.79 (dd,1H,H-2); 6.5 (br,1H,NH); 6.79(d,1H,H-1).

EXAMPLE 21 Preparation of17β-(4-methylpiperidinocarbonyl)-3-oxo-4-aza-5α-androst-1-ene

The process of Example 17 is followed, except that17β-(4-methylpiperidinocarbonyl)-3-oxo-4-aza-5α-androstane is used asstarting substance to give the title compound in a yield of 75%, m.p.:318°-324° C.

EXAMPLE 22 Preparation of17β-(3,3-dimethylpiperidinocarbonyl)-3-oxo-4-aza-5α-androst-1-ene

The process of Example 17 is followed, except that17β-(3,3-dimethylpiperidinocarbonyl)-3-oxo-4-aza-5α-androstane is usedas starting substance to obtain the title compound in a yield of 73%,m.p.: 278°-282° C.

EXAMPLE 23 Preparation of17β-(4,4-pentamethylenepiperidinocarbonyl)-3-oxo-4-aza-5α- androst-1-ene

The process of Example 17 is followed, except that17β-(4,4-pentamethylenepiperidinocarbonyl)-3-oxo-4-aza-5α-androstane isused as starting substance to give the title compound in a yield of 75%,m.p.: 308°-311° C.

EXAMPLE 24 Preparation of17β-(2,6-dimethylpiperidinocarbonyl)-3-oxo-4-aza-5α-androsta-1,16-diene

The process of Example 17 is followed, except that17β-(2,6-dimethylpiperidinocarbonyl)-3-oxo-4-aza-5α-androst-16-ene isused as starting substance to give the title compound in a yield of 62%,m.p.: 288°-290° C.

¹ H-NMR (300 MHz, CDCl₃) δ ppm: 1.01 (s,3H,19-CH₃); 1.10 (s,3H,18-CH₃);1.24 and 1.25 (2*d,6H,CH-CH₃); 2.05 and 2.23 (2*m,2H,H-15); 3.35 (m,1H,H-5); 4.00-5.1 (vbr,2H,NCH-CH₃); 5.71 (m,1H,H-16); 5.80 (dd,1H,H-2);6.19 (br,1H,NH); 6.80 (d,1H,H-1).

EXAMPLE 25 Preparation of17β-(2,5-dimethylpyrrolidinocarbonyl)-3-oxo-4-aza-5α-androsta-1,16-diene

The process of Example 17 is followed, except that17β-(2,5-dimethylpyrrolidinocarbonyl)-3-oxo-4-aza-5α-androst-16-ene isused as starting substance to obtain the title compound in a yield of57%, m.p.: 284°-287° C.

¹ H-NMR (300 MHz, CDCl₃) δ ppm: 1.01 (s,3H,19-CH₃); 1.12 (s,3H,18-CH₃);1.22 and 1.29 (2*d,6H,CH-CH₃); 2.05 and 2.24 (m,2H, H-15); 3.35(m,1H,H-5); 3.95-4.18 (m,2H,NCH-CH₃); 5.82 (dd,1H,H-2); 5.87(m,1H,H-16); 6.24 (br,1H,NH); 6.81 (d,1H,H-1).

EXAMPLE 26 Preparation of17β-(2,6-dimethylpiperidinocarbonyl)-4-methyl-3-oxo-4-aza-5α-androstane

The process of Example 13 is followed, except that17β-(2,6-dimethylpiperidinocarbonyl)-4-methyl-3-oxo-4-aza-5α-androst-16-eneis used as starting substance to obtain the title compound in a yield of88%, m.p.: 200°-203° C.

¹ H-NMR (60 MHz, CDCl₃) δ ppm: 0.71 (s,3H,18-CH₃); 0.90 (s,3H,19-CH₃);1.21 (d,6H,CH-CH₃); 2.92 (s,3H,NCH₃); 3.05 (dd,1H,H-5); 4.0-5.0(2*vbr,2H,2*NCH-CH₃); 6.12 (br, 1H,NH).

EXAMPLE 27 Preparation of17β-(heptamethyleneiminocarbonyl)-4-methyl-3-oxo-4-aza-5α-androstane

The process of Example 13 is followed, except that17β-(heptamethyleneiminocarbonyl)-4-methyl-3-oxo-4-aza-5α-androst-16-eneis used as starting substance to give the title compound in a yield of85%, m.p.: 126°-129° C.

¹ H-NMR (60 MHz, CDCl₃) δ ppm: 0.83 (s,3H,18-CH₃); 0.91 (s,3H,19-CH₃);2.94 (s,3H,NCH₃); 2.8-4.1 (m,5H,H-5 and NCH₂).

EXAMPLE 28 Preparation of17β-(hexamethyleneiminocarbonyl)-4-methyl-3-oxo-4-aza-5α-androstane

The process of Example 13 is followed, except that17β-(hexamethyleneiminocarbonyl)-4-methyl-3-oxo-4-aza-5α-androst-16-eneis used as starting substance to obtain the title compound in a yield of87%, m.p.: 135°-137° C.

¹ H-NMR (60 MHz, CDCl₃) δ ppm: 0.80 (s,3H,18-CH₃); 0.91 (s,3H,19-CH₃);2.94 (s,3H,NCH₃); 2.8-4.1 (m,5H,H-5 and NCH₂).

EXAMPLE 29 Preparation of an Oily Injectable Solution

The active ingredient is dissolved in the mixture of benzyl benzoate andcastor oil suitable for preparing injectable solution, then the solutionis filled up to the desired volume with castor oil. Subsequently, thesolution is filtered until free from bacteria and strange materials,then filled into ampoules and sterilized by heat.

The components of a composition of 1 ml volume are as follows:

    ______________________________________                                        Active ingredient        50 mg                                                Benzyl benzoate         120 mg                                                Castor oil filled up to  1 ml.                                                ______________________________________                                    

Instead of castor oil sunflower oil may also be used with the sameresult.

What is claimed is:
 1. A compound of the Formula (I) ##STR5## wherein Ris hydrogen;R¹ and R² are each methyl or one of R¹ or R² is hydrogen andthe other is methyl; and n is 4 or
 5. 2. The compound of the Formula (I)defined in claim 1 selected from the group consistingof:17beta-(4-methylpiperidinocarbonyl)-3-oxo-4-aza-5alpha-androst-1-ene;17beta-(3,3-dimethylpiperidinocarbonyl)-3-oxo-4-aza-5alpha-androst-1-ene;and17-beta-(2,6-dimethylpiperidinocarbonyl)-3-oxo-4-aza-5alpha-androst-1-ene.3. The compound of the Formula (I) defined in claim 1 which is17beta-(4-methylpiperidinocarbonyl)-3-oxo-4-aza-5alpha-androst-1-ene. 4.A pharmaceutical composition with 5 alpha reductase enzyme inhibitingeffect which comprises as active ingredient effective amount of acompound of the Formula (I) as defined in claim 1 in admixture with apharmaceutically acceptable inert carrier.
 5. A method for treating acnein a mammalian subject which comprises the step of administering to saidsubject an anti-acne effective amount of a compound of the Formula (I)as defined in claim 1.